Raycroft Mark A R, Chauvin Jean-Philippe R, Galliher Matthew S, Romero Kevin J, Stephenson Corey R J, Pratt Derek A
Department of Chemistry and Biomolecular Sciences , University of Ottawa , Ottawa , ON K1N 6N5 , Canada . Email:
Department of Chemistry , University of Michigan , Ann Arbor , MI 48109 , USA . Email:
Chem Sci. 2020 May 6;11(22):5676-5689. doi: 10.1039/d0sc02020f. eCollection 2020 Jun 14.
Hydrogen atom transfer (HAT) is the mechanism by which the vast majority of radical-trapping antioxidants (RTAs), such as hindered phenols, inhibit autoxidation. As such, at least one weak O-H bond is the key structural feature which underlies the reactivity of phenolic RTAs. We recently observed that quinone methide dimers (QMDs) synthesized from hindered phenols are significantly more reactive RTAs than the phenols themselves despite lacking O-H bonds. Herein we describe our efforts to elucidate the mechanism by which they inhibit autoxidation. Four possible reaction paths were considered: (1) HAT from the C-H bonds on the carbon atoms which link the quinone methide moieties; (2) tautomerization or hydration of the quinone methide(s) followed by HAT from the resultant phenolic O-H; (3) direct addition of peroxyl radicals to the quinone methide(s), and (4) homolysis of the weak central C-C bond in the QMD followed by combination of the resultant persistent phenoxyl radicals with peroxyl radicals. The insensitivity of the reactivity of the QMDs to substituent effects, solvent effects and a lack of kinetic isotope effects rule out the HAT reactions (mechanisms 1 and 2). Simple (monomeric) quinone methides, to which peroxyl radicals add, were found to be 100-fold less reactive than the QMDs, ruling out mechanism 3. These facts, combined with the poor RTA activity we observe for a QMD with a stronger central C-C bond, support mechanism 4. The lack of solvent effects on the RTA activity of QMDs suggests that they may find application as additives to materials which contain H-bonding accepting moieties that can dramatically suppress the reactivity of conventional RTAs, such as phenols. This reactivity does not extend to biological membranes owing to the increased microviscosity of the phospholipid bilayer, which suppresses QMD dissociation in favour of recombination. Interestingly, the simple QMs were found to be very good RTAs in phospholipid bilayers - besting even the most potent form of vitamin E.
氢原子转移（HAT）是绝大多数自由基捕获抗氧化剂（RTA）（如受阻酚）抑制自氧化的机制。因此，至少一个弱O-H键是酚类RTA反应活性的关键结构特征。我们最近观察到，由受阻酚合成的醌甲基化物二聚体（QMD）尽管缺乏O-H键，但作为RTA的反应活性比酚本身显著更高。在此，我们描述了为阐明它们抑制自氧化的机制所做的努力。考虑了四种可能的反应路径：（1）从连接醌甲基部分的碳原子上的C-H键进行氢原子转移；（2）醌甲基的互变异构或水合作用，随后从生成的酚羟基进行氢原子转移；（3）过氧自由基直接加成到醌甲基上，以及（4）QMD中弱的中心C-C键均裂，随后生成的持久性苯氧基自由基与过氧自由基结合。QMD反应活性对取代基效应、溶剂效应不敏感以及缺乏动力学同位素效应排除了氢原子转移反应（机制1和2）。发现过氧自由基加成的简单（单体）醌甲基的反应活性比QMD低100倍，排除了机制3。这些事实，再加上我们观察到具有更强中心C-C键的QMD的RTA活性较差，支持了机制4。溶剂对QMD的RTA活性缺乏影响表明，它们可能作为添加剂应用于含有氢键接受基团的材料中，这些基团可以显著抑制传统RTA（如酚）的反应活性。由于磷脂双层的微粘度增加，这种反应活性不会扩展到生物膜，这抑制了QMD的解离而有利于重组。有趣的是，发现简单的QM在磷脂双层中是非常好的RTA——甚至优于最有效的维生素E形式。
